Tre a t m e n t o f I n t r a c e re b r a l Hemorrhage Associated with New Oral Anticoagulant Use The Neurologist’s View Roland Veltkamp,
a,b, *, MD, FESO
Solveig Horstmann,
MD
b
KEYWORDS Intracerebral hemorrhage Warfarin Oral anticoagulation New oral anticoagulants KEY POINTS The mortality rate associated with intracerebral hemorrhage (ICH) in patients treated with oral anticoagulants (OAC-ICH) is high. Secondary hematoma enlargement is one of the main reasons for poor outcome in patients with OAC-ICH. The key therapeutic target in OAC-ICH is rapid restoration of normal coagulation. In ICH associated with vitamin K antagonist therapy, hemostatic factors can be used. Optimal management of ICH associated with new direct OAC treatment is currently unknown.
INTRODUCTION
Intracerebral hemorrhage (ICH) associated with the use of oral anticoagulants (OAC-ICH) is an increasingly frequent challenge for emergency management. This mini-review summarizes the epidemiology of and predisposing factors for OAC-ICH. Current recommendations are reviewed for the management of OAC-ICH in patients using vitamin K antagonists (VKAs) or new direct oral anticoagulants (NOACs).
Disclosure Statement: R. Veltkamp has received consulting honoraria, research support, travel grants, and speakers’ honoraria from Bayer HealthCare, Boehringer Ingelheim, Bristol-Myers Squibb, Pfizer, Roche Diagnostics Corporation, CSL Behring, St. Jude Medical, and Sanofi-Aventis. S. Horstmann is supported by an Olympia Morata Fellowship of the Medical Faculty, University of Heidelberg, Germany. a Department of Stroke Medicine, Charing Cross Hospital, Imperial College London, Fulham Palace Road, London W6 8RF, UK; b Department of Neurology, University of Heidelberg, INF 400, Heidelberg 69120, Germany * Corresponding author. Department of Stroke Medicine, Charing Cross Hospital, Imperial College London, Fulham Palace Road, London SW, UK. E-mail address: [email protected] Clin Lab Med - (2014) -–http://dx.doi.org/10.1016/j.cll.2014.06.007
labmed.theclinics.com
0272-2712/14/$ – see front matter Crown Copyright Ó 2014 Published by Elsevier Inc. All rights reserved.
2
Veltkamp & Horstmann
Abbreviations AF aPCC APOE ICH INR NOAC OAC-ICH PCC rFVIIa VKA
Atrial fibrillation Activated PCC Apolipoprotein E Intracerebral hemorrhage International normalized ratio New direct oral anticoagulant Intracerebral hemorrhage associated with the use of oral anticoagulants Prothrombin complex concentrate Recombinant activated factor VII Vitamin K antagonists
EPIDEMIOLOGY AND PROGNOSIS OF OAC-ICH
Older epidemiologic studies suggest that OAC-ICH associated with VKA treatment occurs at a rate of 2 to 9 per 100,000 population per year.1 The incidence of OACICH is 7- to 10-fold higher than the incidence of ICH in patients who do not receive OACs.1 Furthermore, the incidence of OAC-ICH has increased considerably over the past few years, reaching 12% to 15% in the general population, and up to 24% in tertiary care centers.2–6 This increase reflects the increasing prevalence of atrial fibrillation (AF) in aging populations,7–10 which is the predominant reason for longterm oral anticoagulation. Currently, 1% to 2% of the general population have AF.7 The rate of ICH in patients treated with VKAs is up to 1.8% per year.11,12 The rate of ICH during treatment with NOACs is 40% to 70% lower compared with warfarin, based on results from 4 large trials of stroke prevention in patients with AF.8,13,14 Mortality rates in patients with OAC-ICH range from 52% to 67%, and are higher than those observed in patients with spontaneous ICH without OAC therapy.15 Survivors of OAC-ICH also more frequently remain severely disabled compared with patients recovering from spontaneous ICH unrelated to OAC therapy.3,4,11 OAC-ICH is responsible for 60% to 90% of all bleeding-associated deaths in patients receiving VKA therapy.16,17 Based on data from the RE-LY trial, mortality seems to be as high in ICH associated with NOAC therapy as in ICH during VKA treatment.18 PREDISPOSING FACTORS FOR OAC-ICH
Spontaneous ICH and OAC-ICH share the same risk factors. Advanced age, hypertension, and previous ischemic stroke have the strongest association with ICH.19 Up to 70% of ICH is attributed to hypertensive small penetrating vessel arteriopathy, whereas cerebral amyloid angiopathy is associated with 5% to 20% of ICH cases.20 Additional risk factors for OAC-ICH are concomitant use of aspirin, smoking, alcohol consumption, and severe heart and liver disease.21–23 The risk of ICH during anticoagulation therapy increases markedly when the international normalized ratio (INR) exceeds 4,24 whereas the estimated annual risk of OAC-ICH is 0.3% to 3.7% when the target INR is between 2.0 and 4.5.1 Each increase in the INR by 0.5 increases the bleeding risk by a factor of 1.4 and, although the intensity of anticoagulation therapy is related to a greater risk of OAC-ICH,24–26 most ICH associated with VKA treatment occurs while patients are in the therapeutic range (ie, INR 2–3).6 Data from epidemiologic studies of ICH in patients undergoing NOAC treatment are not yet available. One further aspect of the risk factors for ICH is the hematoma location. For example, strong evidence shows that genetic risk factors influence ICH location and, in genetic
Treatment of Intracerebral Hemorrhage
association studies, apolipoprotein E (APOE) ε2 more than APOE ε4 was associated with lobar hemorrhage.27–29 The individual risk of experiencing any bleeding event when using a VKA can be determined using the HAS-BLED score30; evidence suggests that the score also moderately correlates with ICH risk.31 The use of cerebral microbleeds detected on magnetic resonance imaging as indicators of an increased risk of hemorrhagic complications is currently under investigation.32 EMERGENCY TREATMENT OF ICH ASSOCIATED WITH VKA THERAPY
Hematoma size is a major prognostic factor in ICH because early secondary hematoma growth occurs in approximately one-third of patients experiencing a spontaneous ICH without OAC and is even more frequent in patients with OAC-ICH.3,4,11 Therefore, prevention of hematoma expansion is a major therapeutic target. Another factor determining prognosis after ICH is expansion of the hematoma into the ventricles, which is more frequent and prolonged in patients receiving OACs.6,33 The use of VKAs reduces the plasma level of the clotting factors II, VII, IX, and X, but also of the anticoagulant proteins C and S. The anticoagulant effect of VKAs can be measured easily by routine coagulation tests (eg, INR), and point-of-care testing is available in emergency settings, allowing for prompt initiation and monitoring of reversal with coagulation factor concentrates.34,35 In ICH associated with VKA therapy, coagulation can be restored by substitution of hemostatic factors using prothrombin complex concentrate (PCC) or fresh frozen plasma.36–39 Because the efficacy and safety of these treatments have not been evaluated in randomized controlled trials in patients with OAC-ICH,40,41 the recommendation to reverse VKAinduced anticoagulation with these agents during ICH is mainly based on plausibility and expert opinion. EMERGENCY TREATMENT OF ICH ASSOCIATED WITH NOAC THERAPY
NOACs inhibit either factor Xa (rivaroxaban, apixaban, edoxaban), which is responsible for the generation of thrombin from prothrombin, or thrombin (factor IIa; dabigatran), which converts fibrinogen to fibrin.42,43 The mechanism of action of NOACs differs substantially from that of VKAs, as described previously and in other articles elsewhere in this issue by Samama and colleagues and van Ryn and colleagues. The onset of anticoagulation occurs within 1 to 4 hours after first dosing, and the anticoagulant effect of NOACs is much shorter than that of VKAs. NOACs have limited interaction with other drugs44 and none with food. The anticoagulant effect does not require monitoring and, unlike VKAs, dose-adjustments are usually unnecessary. NOAC-specific antidotes are in preclinical and clinical testing, but they are not yet available in routine practice.45,46 It is currently unknown whether NOACs increase the risk of secondary hematoma enlargement in ICH compared with non-anticoagulated patients. In a murine collagenase injection model of OAC-ICH, high doses of dabigatran or rivaroxaban led to excess hematoma expansion,47,48 whereas another study with lower doses of dabigatran reported no effect.49 Despite the current uncertainty, most stroke specialists assume that ICH occurring during NOAC therapy confers an additional risk of hematoma expansion.50–52 Consequently, prevention of hematoma expansion is considered a major therapeutic target in ICH associated with NOACs. Comparable to the treatment of ICH during VKA treatment, reversal of the anticoagulant effect of NOACs using hemostatic factors may be an effective approach to treat ICH during NOAC treatment as well.47,48 However, no specific antidote is currently
3
4
Veltkamp & Horstmann
available to reverse the activity of NOACs in major bleeding, including ICH, and coagulation tests may not be predictive of bleeding (Table 1). Moreover, laboratory monitoring procedures have not been established to assess the effectiveness of nonspecific hemostatic reversal agents for NOACs. Further details on this topic have been extensively addressed in the 15 articles included in this issue. The activated partial thromboplastin time provides a qualitative assessment of dabigatran levels. However, the sensitivity of different reagents used in this assay varies widely. The anticoagulant effect of dabigatran can also be quantified by the diluted thrombin time and the ecarin clotting time, as discussed by van Ryn and colleagues elsewhere in this issue. Anticoagulation induced by rivaroxaban and apixaban can be assessed using prothrombin time when specific reagents are used (eg, neoplastin) (see Table 1). However, the anticoagulant effect of these factor Xa inhibitors is best evaluated through measuring substance-specific anti–factor Xa activity (see Table 1 and the article by Samama and colleagues in this issue). In experimental studies of ICH associated with NOAC treatment, PCCs and, less consistently, fresh frozen plasma and recombinant activated factor VII (rFVIIa) prevented excess hematoma enlargement.47,48 A study in healthy human volunteers reported that PCC (50 U/kg) completely normalized prolongation of the prothrombin time after pretreatment with rivaroxaban, but had no effect on coagulation tests that were altered after the intake of dabigatran.53 Administration of activated PCC (aPCC) to healthy volunteers pretreated with rivaroxaban, apixaban, or dabigatran had a more profound effect on coagulation parameters than PCC.54 However, whether these parameters sufficiently reflect the effects of these reversal agents on the coagulation system in patients with ICH remains to be shown. Current Treatment Recommendations
Current treatment recommendations for the management of ICH associated with NOAC use are based on expert opinion (Fig. 1).55–57 In patients presenting with ICH, NOAC treatment should be discontinued. Because of the short half-lives of Table 1 Laboratory diagnostics
aPTT
Dabigatran
Rivaroxaban
Apixaban
[[
[([)
[
PT
[
[ to [[
[
Quick test
Y
Y to YY
Y
INR
([)
[ to [[
[
TT
[[[[
4
([)
ECT
[[[[
4
4
Anti–factor Xa Activity
4 to [
[[[
[[[
Peak value test
aPTT
Anti–factor Xa activity (PT, aPTT)
Anti–factor Xa activity (PT, aPTT)
Trough test
TT
Anti–factor Xa activity
Anti–factor Xa activity
Substance-specific test system
Hemoclot, dabigatran concentration
Anti–factor Xa activity (calibrated)
Anti–factor Xa activity (calibrated)
[, Prolonged/increased; ([), may be prolonged/increased; Y, decreased; 4, equal/no change. Abbreviations: aPTT, activated partial thromboplastin time; ECT, ecarin clotting time; PT, prothrombin time; TT, thrombin time.
Treatment of Intracerebral Hemorrhage
Acute ICH with known or suspected intake of NOACs ≤ 48 h
Standard coagulation in ER: aPTT, INR, TT +
Additional coagulation tests
Dabigatran +
+
Dabigatranconcentration
Rivaroxaban +
Factor-Xa Rivaroxaban
Apixaban +
Factor-Xa Apixaban
PCC: 30-50 IU/kg (repeated doses , 1-2x, can be considered) aPCC: 50 IE/kg max. 200 IE/kg/day halt NOACs; control aPTT, INR, TT; lower blood pressure syst.
a,b, *, MD, FESO
Solveig Horstmann,
MD
b
KEYWORDS Intracerebral hemorrhage Warfarin Oral anticoagulation New oral anticoagulants KEY POINTS The mortality rate associated with intracerebral hemorrhage (ICH) in patients treated with oral anticoagulants (OAC-ICH) is high. Secondary hematoma enlargement is one of the main reasons for poor outcome in patients with OAC-ICH. The key therapeutic target in OAC-ICH is rapid restoration of normal coagulation. In ICH associated with vitamin K antagonist therapy, hemostatic factors can be used. Optimal management of ICH associated with new direct OAC treatment is currently unknown.
INTRODUCTION
Intracerebral hemorrhage (ICH) associated with the use of oral anticoagulants (OAC-ICH) is an increasingly frequent challenge for emergency management. This mini-review summarizes the epidemiology of and predisposing factors for OAC-ICH. Current recommendations are reviewed for the management of OAC-ICH in patients using vitamin K antagonists (VKAs) or new direct oral anticoagulants (NOACs).
Disclosure Statement: R. Veltkamp has received consulting honoraria, research support, travel grants, and speakers’ honoraria from Bayer HealthCare, Boehringer Ingelheim, Bristol-Myers Squibb, Pfizer, Roche Diagnostics Corporation, CSL Behring, St. Jude Medical, and Sanofi-Aventis. S. Horstmann is supported by an Olympia Morata Fellowship of the Medical Faculty, University of Heidelberg, Germany. a Department of Stroke Medicine, Charing Cross Hospital, Imperial College London, Fulham Palace Road, London W6 8RF, UK; b Department of Neurology, University of Heidelberg, INF 400, Heidelberg 69120, Germany * Corresponding author. Department of Stroke Medicine, Charing Cross Hospital, Imperial College London, Fulham Palace Road, London SW, UK. E-mail address: [email protected] Clin Lab Med - (2014) -–http://dx.doi.org/10.1016/j.cll.2014.06.007
labmed.theclinics.com
0272-2712/14/$ – see front matter Crown Copyright Ó 2014 Published by Elsevier Inc. All rights reserved.
2
Veltkamp & Horstmann
Abbreviations AF aPCC APOE ICH INR NOAC OAC-ICH PCC rFVIIa VKA
Atrial fibrillation Activated PCC Apolipoprotein E Intracerebral hemorrhage International normalized ratio New direct oral anticoagulant Intracerebral hemorrhage associated with the use of oral anticoagulants Prothrombin complex concentrate Recombinant activated factor VII Vitamin K antagonists
EPIDEMIOLOGY AND PROGNOSIS OF OAC-ICH
Older epidemiologic studies suggest that OAC-ICH associated with VKA treatment occurs at a rate of 2 to 9 per 100,000 population per year.1 The incidence of OACICH is 7- to 10-fold higher than the incidence of ICH in patients who do not receive OACs.1 Furthermore, the incidence of OAC-ICH has increased considerably over the past few years, reaching 12% to 15% in the general population, and up to 24% in tertiary care centers.2–6 This increase reflects the increasing prevalence of atrial fibrillation (AF) in aging populations,7–10 which is the predominant reason for longterm oral anticoagulation. Currently, 1% to 2% of the general population have AF.7 The rate of ICH in patients treated with VKAs is up to 1.8% per year.11,12 The rate of ICH during treatment with NOACs is 40% to 70% lower compared with warfarin, based on results from 4 large trials of stroke prevention in patients with AF.8,13,14 Mortality rates in patients with OAC-ICH range from 52% to 67%, and are higher than those observed in patients with spontaneous ICH without OAC therapy.15 Survivors of OAC-ICH also more frequently remain severely disabled compared with patients recovering from spontaneous ICH unrelated to OAC therapy.3,4,11 OAC-ICH is responsible for 60% to 90% of all bleeding-associated deaths in patients receiving VKA therapy.16,17 Based on data from the RE-LY trial, mortality seems to be as high in ICH associated with NOAC therapy as in ICH during VKA treatment.18 PREDISPOSING FACTORS FOR OAC-ICH
Spontaneous ICH and OAC-ICH share the same risk factors. Advanced age, hypertension, and previous ischemic stroke have the strongest association with ICH.19 Up to 70% of ICH is attributed to hypertensive small penetrating vessel arteriopathy, whereas cerebral amyloid angiopathy is associated with 5% to 20% of ICH cases.20 Additional risk factors for OAC-ICH are concomitant use of aspirin, smoking, alcohol consumption, and severe heart and liver disease.21–23 The risk of ICH during anticoagulation therapy increases markedly when the international normalized ratio (INR) exceeds 4,24 whereas the estimated annual risk of OAC-ICH is 0.3% to 3.7% when the target INR is between 2.0 and 4.5.1 Each increase in the INR by 0.5 increases the bleeding risk by a factor of 1.4 and, although the intensity of anticoagulation therapy is related to a greater risk of OAC-ICH,24–26 most ICH associated with VKA treatment occurs while patients are in the therapeutic range (ie, INR 2–3).6 Data from epidemiologic studies of ICH in patients undergoing NOAC treatment are not yet available. One further aspect of the risk factors for ICH is the hematoma location. For example, strong evidence shows that genetic risk factors influence ICH location and, in genetic
Treatment of Intracerebral Hemorrhage
association studies, apolipoprotein E (APOE) ε2 more than APOE ε4 was associated with lobar hemorrhage.27–29 The individual risk of experiencing any bleeding event when using a VKA can be determined using the HAS-BLED score30; evidence suggests that the score also moderately correlates with ICH risk.31 The use of cerebral microbleeds detected on magnetic resonance imaging as indicators of an increased risk of hemorrhagic complications is currently under investigation.32 EMERGENCY TREATMENT OF ICH ASSOCIATED WITH VKA THERAPY
Hematoma size is a major prognostic factor in ICH because early secondary hematoma growth occurs in approximately one-third of patients experiencing a spontaneous ICH without OAC and is even more frequent in patients with OAC-ICH.3,4,11 Therefore, prevention of hematoma expansion is a major therapeutic target. Another factor determining prognosis after ICH is expansion of the hematoma into the ventricles, which is more frequent and prolonged in patients receiving OACs.6,33 The use of VKAs reduces the plasma level of the clotting factors II, VII, IX, and X, but also of the anticoagulant proteins C and S. The anticoagulant effect of VKAs can be measured easily by routine coagulation tests (eg, INR), and point-of-care testing is available in emergency settings, allowing for prompt initiation and monitoring of reversal with coagulation factor concentrates.34,35 In ICH associated with VKA therapy, coagulation can be restored by substitution of hemostatic factors using prothrombin complex concentrate (PCC) or fresh frozen plasma.36–39 Because the efficacy and safety of these treatments have not been evaluated in randomized controlled trials in patients with OAC-ICH,40,41 the recommendation to reverse VKAinduced anticoagulation with these agents during ICH is mainly based on plausibility and expert opinion. EMERGENCY TREATMENT OF ICH ASSOCIATED WITH NOAC THERAPY
NOACs inhibit either factor Xa (rivaroxaban, apixaban, edoxaban), which is responsible for the generation of thrombin from prothrombin, or thrombin (factor IIa; dabigatran), which converts fibrinogen to fibrin.42,43 The mechanism of action of NOACs differs substantially from that of VKAs, as described previously and in other articles elsewhere in this issue by Samama and colleagues and van Ryn and colleagues. The onset of anticoagulation occurs within 1 to 4 hours after first dosing, and the anticoagulant effect of NOACs is much shorter than that of VKAs. NOACs have limited interaction with other drugs44 and none with food. The anticoagulant effect does not require monitoring and, unlike VKAs, dose-adjustments are usually unnecessary. NOAC-specific antidotes are in preclinical and clinical testing, but they are not yet available in routine practice.45,46 It is currently unknown whether NOACs increase the risk of secondary hematoma enlargement in ICH compared with non-anticoagulated patients. In a murine collagenase injection model of OAC-ICH, high doses of dabigatran or rivaroxaban led to excess hematoma expansion,47,48 whereas another study with lower doses of dabigatran reported no effect.49 Despite the current uncertainty, most stroke specialists assume that ICH occurring during NOAC therapy confers an additional risk of hematoma expansion.50–52 Consequently, prevention of hematoma expansion is considered a major therapeutic target in ICH associated with NOACs. Comparable to the treatment of ICH during VKA treatment, reversal of the anticoagulant effect of NOACs using hemostatic factors may be an effective approach to treat ICH during NOAC treatment as well.47,48 However, no specific antidote is currently
3
4
Veltkamp & Horstmann
available to reverse the activity of NOACs in major bleeding, including ICH, and coagulation tests may not be predictive of bleeding (Table 1). Moreover, laboratory monitoring procedures have not been established to assess the effectiveness of nonspecific hemostatic reversal agents for NOACs. Further details on this topic have been extensively addressed in the 15 articles included in this issue. The activated partial thromboplastin time provides a qualitative assessment of dabigatran levels. However, the sensitivity of different reagents used in this assay varies widely. The anticoagulant effect of dabigatran can also be quantified by the diluted thrombin time and the ecarin clotting time, as discussed by van Ryn and colleagues elsewhere in this issue. Anticoagulation induced by rivaroxaban and apixaban can be assessed using prothrombin time when specific reagents are used (eg, neoplastin) (see Table 1). However, the anticoagulant effect of these factor Xa inhibitors is best evaluated through measuring substance-specific anti–factor Xa activity (see Table 1 and the article by Samama and colleagues in this issue). In experimental studies of ICH associated with NOAC treatment, PCCs and, less consistently, fresh frozen plasma and recombinant activated factor VII (rFVIIa) prevented excess hematoma enlargement.47,48 A study in healthy human volunteers reported that PCC (50 U/kg) completely normalized prolongation of the prothrombin time after pretreatment with rivaroxaban, but had no effect on coagulation tests that were altered after the intake of dabigatran.53 Administration of activated PCC (aPCC) to healthy volunteers pretreated with rivaroxaban, apixaban, or dabigatran had a more profound effect on coagulation parameters than PCC.54 However, whether these parameters sufficiently reflect the effects of these reversal agents on the coagulation system in patients with ICH remains to be shown. Current Treatment Recommendations
Current treatment recommendations for the management of ICH associated with NOAC use are based on expert opinion (Fig. 1).55–57 In patients presenting with ICH, NOAC treatment should be discontinued. Because of the short half-lives of Table 1 Laboratory diagnostics
aPTT
Dabigatran
Rivaroxaban
Apixaban
[[
[([)
[
PT
[
[ to [[
[
Quick test
Y
Y to YY
Y
INR
([)
[ to [[
[
TT
[[[[
4
([)
ECT
[[[[
4
4
Anti–factor Xa Activity
4 to [
[[[
[[[
Peak value test
aPTT
Anti–factor Xa activity (PT, aPTT)
Anti–factor Xa activity (PT, aPTT)
Trough test
TT
Anti–factor Xa activity
Anti–factor Xa activity
Substance-specific test system
Hemoclot, dabigatran concentration
Anti–factor Xa activity (calibrated)
Anti–factor Xa activity (calibrated)
[, Prolonged/increased; ([), may be prolonged/increased; Y, decreased; 4, equal/no change. Abbreviations: aPTT, activated partial thromboplastin time; ECT, ecarin clotting time; PT, prothrombin time; TT, thrombin time.
Treatment of Intracerebral Hemorrhage
Acute ICH with known or suspected intake of NOACs ≤ 48 h
Standard coagulation in ER: aPTT, INR, TT +
Additional coagulation tests
Dabigatran +
+
Dabigatranconcentration
Rivaroxaban +
Factor-Xa Rivaroxaban
Apixaban +
Factor-Xa Apixaban
PCC: 30-50 IU/kg (repeated doses , 1-2x, can be considered) aPCC: 50 IE/kg max. 200 IE/kg/day halt NOACs; control aPTT, INR, TT; lower blood pressure syst.
